DESCRIPTION: (Applicant's abstract) Relatively brief periods of ongoing (sec - min) afferent nociceptive stimulation, as evoked with subcutaneous injection of formalin, will (i) evoke an acute afferent barrage which correlates with the acute behavioral response and ii) trigger a long lasting facilitation of spinal nociceptive processing in which a minimum stimulus yields an exaggerated pain state (hyperalgesia). Specific pharmacological interventions with spinal agents have suggested that the hyperalgesic component may be mediated by activation of spinal excitatory amino acid (EAA) and prostanoid (PG) receptors and the production of nitric oxide (NO). The observed pharmacological correlates of the behavioral consequences of acute injury yields several specific hypotheses: 1) Tissue injury (as with formalin) leads to the acute activation of spinal substance P (SP) and glutamate receptors. 2) Activation of glutamate receptors of the NMDA and nonNMDA type and SP receptors of the NK1 type evoke the subsequent formation of COX (cyclo-oxygenase) and NOS (nitric oxide synthase) products. 3) Spinal COX and NOS products enhance the release of EAA. This cascade suggests that activation of glutamate or SP receptors by endogenous release will evoke NO and PG release from spinal cord and that event will subsequently enhance glutamate release. 4) Over longer intervals of afferent activation (min-hrs) as generated by inflamed knee joints, spinal COX and NOS, under the control of circulating corticoids, may display induction, yielding enzymes with a distinct inhibitor-drug profile. Such induction would yield increased PG and NO, an increased release of spinal glutamate and a hyperalgesia with a pharmacology distinct from that observed with short term (sec-min) stimulation. To address these hypotheses, we will investigate the extra-cellular levels of EAA, NO and PGs, using in vivo lumbar intrathecal dialysis in the unanesthetized rat and correlate these with changes in "pain" behavior. The pharmacology of this release and concurrent changes in behavior will be characterized by the spinal delivery of receptor-preferring agonists/antagonists and inhibitors. This work elucidates spinal systems mediating the profound changes in processing noted in a post injury state. Aside from an appreciation of the role played by novel spinal systems in pain processing and their plasticity in the face of afferent activation, protracted afferent drive is a pervasive component of a post-injury pain state. Elucidation of these mechanisms has relevance to the evolution of pharmacotherapy for its control in humans.